DE102011113059A1 - Therapeutic Applications of Ectoin - Google Patents
Therapeutic Applications of Ectoin Download PDFInfo
- Publication number
- DE102011113059A1 DE102011113059A1 DE102011113059A DE102011113059A DE102011113059A1 DE 102011113059 A1 DE102011113059 A1 DE 102011113059A1 DE 102011113059 A DE102011113059 A DE 102011113059A DE 102011113059 A DE102011113059 A DE 102011113059A DE 102011113059 A1 DE102011113059 A1 DE 102011113059A1
- Authority
- DE
- Germany
- Prior art keywords
- ectoine
- inflammation
- composition according
- composition
- treatment
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 230000001225 therapeutic effect Effects 0.000 title 1
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- KIIBBJKLKFTNQO-WHFBIAKZSA-N 5-hydroxyectoine Chemical compound CC1=N[C@H](C(O)=O)[C@@H](O)CN1 KIIBBJKLKFTNQO-WHFBIAKZSA-N 0.000 claims abstract description 22
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Abstract
Die Erfindung betrifft eine Zusammensetzung enthaltend Ectoin, Hydroxyectoin und/oder ein Salz, Ester oder Amid dieser Verbindungen zur Unterdrückung von anti-apoptotischen Signalen auf neutrophile Granulozyten und andere an Entzündungen beteiligte Zellen. Die verzögerte Apoptose der Neutrophilen ist eine Hauptkomponente für verschiedene Arten von Entzündungen. Durch Verabreichung von Ectoin wird eine zumindest partielle Wiederherstellung der normalen Apoptoserate erreicht, was mit einer entsprechenden Verbesserung der Entzündungserscheinungen verbunden ist.The invention relates to a composition comprising ectoine, hydroxyectoine and / or a salt, ester or amide of these compounds for the suppression of anti-apoptotic signals on neutrophilic granulocytes and other cells involved in inflammation. Delayed apoptosis of neutrophils is a major component of various types of inflammation. Administration of ectoine achieves at least partial recovery of the normal rate of apoptosis, associated with a concomitant improvement in inflammatory effects.
Description
Die Erfindung betrifft Zusammensetzungen, enthaltend Ectoin, Hydroxyectoin oder entsprechende Salze, Ester und Amide.The invention relates to compositions containing ectoine, hydroxyectoine or corresponding salts, esters and amides.
Osmolyte bzw. kompatible Solute aus extremophilen Mikroorganismen bilden eine bekannte Gruppe niedermolekularer Schutzstoffe. Extremophile sind sehr außergewöhnliche Mikroorganismen, da sie optimal bzw. bei hohen Salzkonzentrationen (bis 200 g NaCl/l) und hohen Temperaturen (60 bis 110°C) wachsen, die bei mesophilen (normalen) Organismen zu massiven Schädigungen zellulärer Strukturen führen würden. In den letzten Jahren wurde daher ein großer Forschungsaufwand betrieben, um die biochemischen Komponenten zu identifizieren, die zu der bemerkenswerten Stabilisierung der Zellstrukturen führen. Obwohl viele Enzyme aus hyperthermophilen Mikroorganismen auch unter hohen Temperaturen stabil sind, gilt dies nicht generell für die zellulären Strukturen thermo- und hyperthermophiler Organismen. Zu der hohen Temperaturstabilität von Zellstrukturen tragen in erheblichem Maße niedermolekulare organische Substanzen (kompatible Solute, Osmolyte) im intrazellulären Milieu bei. Verschiedene neuartige Osmolyte konnten in den letzten Jahren in extremophilen Mikroorganismen erstmals identifiziert werden. In einigen Fallen konnte der Beitrag dieser Verbindungen zum Schutz zellulärer Strukturen – vor allem Enzymen – gegenüber Hitze und Trockenheit bereits gezeigt werden (
Für eine Reihe von kompatiblen Soluten haben sich sinnvolle Anwendungsmöglichkeiten im medizinischen, kosmetischen und biologischen Bereich ergeben. Zu den wichtigsten kompatiblen Soluten zählen dabei das Ectoin (2-Methyl-1,4,5,6-tetrahydropyrimidin-4-carbonsäure) und seine Derivate. So wird beispielsweise in der
Die Struktur des natürlichen L-Ectoins((S)-2-Methyl-1,4,5,6-tetrahydropyrimidin-4-carbonsäure) ist im Folgenden dargestellt: The structure of the natural L-ectoine ((S) -2-methyl-1,4,5,6-tetrahydropyrimidine-4-carboxylic acid) is shown below:
Auch das Hydroxyectoin wurde als für verschiedene Zwecke vorteilhaft beschrieben. Die Struktur des natürlichen Hydroxyectoins((4S, 5S)-5-Hydroxy-2-methyl-1,4,5,6-tetrahydropyrimidin-4-carbonsäure) wird im Folgenden wiedergegeben: Hydroxyectoine has also been described as beneficial for various purposes. The structure of the natural hydroxyectoine ((4S, 5S) -5-hydroxy-2-methyl-1,4,5,6-tetrahydropyrimidine-4-carboxylic acid) is shown below:
Die Behandlung von auf Schwebstaubeinwirkung beruhenden Lungenkrankheiten und kardiovaskulären Erkrankungen ist Gegenstand des europäischen Patents
Bei vielen Entzündungserscheinungen spielen neutrophile Granulozyten, kurz Neutrophile, eine wichtige Rolle, insbesondere in der Bekämpfung von viralen und bakteriellen Pathogenen. Neutrophile werden in hoher Zahl im Knochenmark gebildet. Die Pathogene werden durch Freisetzung von reaktiven Sauerstoffspezies und Enzymen wie Myeloperoxidase, Elastase oder Matrixmetalloproteinasen zerstört. Da diese Reaktionen jedoch mit Nebenwirkungen auf das beteiligte Gewebe verbunden sind, muss eine strikte Regulation erfolgen, so dass die neutrophile Entzündung nicht über die Bekämpfung der eigentlichen Pathogene hinaus andauert. Entsprechend wird eine Signalkaskade aktiviert, die zur Apoptose der neutrophilen Granulozyten führt. Entzündungsmediatoren bewirken jedoch, dass die Apoptose hinausgezögert wird und verlängern auf diese Weise die Lebenszeit der Neutrophile. Die Akkumulation von Neutrophilen und Monozyten am Infektionsort stellt eine der Hauptkomponenten einer Entzündung dar. Die dauerhafte Verzögerung der Apoptose kann bis zu chronischen Entzündungserscheinungen führen. Beispiele sind eine chronische Lungenentzündung oder eine chronisch obstruktive Lungenerkrankung (COPD).In many cases of inflammation neutrophils, neutrophils play an important role, especially in the control of viral and bacterial pathogens. Neutrophils are formed in high numbers in the bone marrow. The pathogens are destroyed by the release of reactive oxygen species and enzymes such as myeloperoxidase, elastase or matrix metalloproteinases. Since these reactions are associated with side effects on the tissue involved, a strict regulation must be carried out so that the neutrophilic inflammation does not last beyond the control of the actual pathogens. Accordingly, a signaling cascade is activated which leads to the apoptosis of the neutrophilic granulocytes. Inflammatory mediators, however, cause apoptosis to be delayed, extending neutrophil lifetimes. The accumulation of neutrophils and monocytes at the site of infection is one of the main components of inflammation. The permanent delay of apoptosis can lead to chronic inflammatory phenomena. Examples are chronic pneumonia or chronic obstructive pulmonary disease (COPD).
Der Schwerpunkt bei der Bekämpfung von chronischen Entzündungen liegt daher in der Bekämpfung der Entzündung, die auf die Akkumulation der Neutrophile zurückzuführen ist. Problematisch macht sich hierbei bemerkbar, dass Neutrophile, anders als andere an einer Entzündung beteiligte Zellen, auf Corticosteroide nur unbefriedigend ansprechen. Wünschenswert wären daher Medikamente, die die anti-apoptotische Wirkung von Entzündungsmediatoren, Corticosteroiden und anderen Stoffen einschränken.The focus in the fight against chronic inflammation therefore lies in the fight against inflammation, which is due to the accumulation of neutrophils. A problem that is noticeable here is that neutrophils, unlike other cells involved in an inflammation, respond to corticosteroids only unsatisfactorily. It would therefore be desirable to have drugs that limit the anti-apoptotic effects of inflammatory mediators, corticosteroids and other substances.
Überraschend hat sich nunmehr herausgestellt, dass die Behandlung mit Ectoin oder Hydroxyectoin die anti-apoptotische Wirkung der Entzündungsmediatoren, Corticosteroide und anderen Stoffen zumindest teilweise aufhebt und auf diese Weise die natürliche Apoptoserate von neutrophilen Granulozyten restauriert, ohne jedoch alleine eine pro-apoptotische Wirkung zu zeigen. Die Erfindung betrifft daher eine Zusammensetzung enthaltend Ectoin, Hydroxyectoin und/oder ein Salz, Ester oder Amid dieser Verbindungen zur Unterdrückung von anti-apoptotischen Signalen auf neutrophile Granulozyten und andere an Entzündungen beteiligte Zellen wie Makrophagen, eosinophile Granulozyten, basophile Granulozyten, Mastzellen, Lymphozyten, Epitheloidzellen und dendritische Zellen. Die Unterdrückung der anti-apoptotischen Signale steht normalerweise im Zusammenhang mit der Behandlung oder Prävention von Entzündungen, wobei chronische Entzündungen hier eine besondere Rolle spielen. Besondere Bedeutung hat die Bekämpfung von Entzündungen, die die Atemwege und die Lunge betreffen, insbesondere Lungenentzündungen, Asthma, chronisch obstruktive Lungenerkrankungen, ARDS, zystische Fibrose, Lungenfibrose, Silikose, Sarkoidose, Allergien und bronchiale Hyperreagibilität.Surprisingly, it has now been found that the treatment with ectoine or hydroxyectoin at least partially abolishes the anti-apoptotic effect of the inflammatory mediators, corticosteroids and other substances and in this way restores the natural rate of apoptosis of neutrophilic granulocytes, but without exhibiting a pro-apoptotic effect alone , The invention therefore relates to a composition comprising ectoine, hydroxyectoine and / or a salt, ester or amide of these compounds for the suppression of anti-apoptotic signals on neutrophilic granulocytes and other inflammatory cells such as macrophages, eosinophilic granulocytes, basophilic granulocytes, mast cells, lymphocytes, Epithelial cells and dendritic cells. The suppression of anti-apoptotic signals is usually associated with the treatment or prevention of inflammation, with chronic inflammation playing a particular role here. Of particular importance is the control of inflammation involving the respiratory tract and lungs, in particular pneumonia, asthma, chronic obstructive pulmonary disease, ARDS, cystic fibrosis, pulmonary fibrosis, silicosis, sarcoidosis, allergies and bronchial hyperresponsiveness.
Die Hemmung der Apoptose der neutrophilen Granulozyten bei den untersuchten Entzündungsreaktionen wird auf eine membranvermittelte Aktivierung von membrangekoppelten Signalwegen über PI3-K (Phosphatidylinositol-3-kinase) zurückgeführt. Diese führen zu einer Aktivierung der Proteinkinase B (AKT) und letztlich zu einem Anstieg des MCI-1-Levels, eines anti-apoptotisch wirkenden Proteins. Es wird vermutet, dass Ectoin die AKT-Aktivierung reduziert.The inhibition of apoptosis of neutrophilic granulocytes in the investigated inflammatory reactions is attributed to a membrane-mediated activation of membrane-coupled signaling pathways via PI3-K (phosphatidylinositol-3-kinase). These lead to activation of protein kinase B (AKT) and ultimately to an increase in the MCI-1 level, an anti-apoptotic protein. Ectoin is thought to reduce AKT activation.
Die neutrophile Entzündungsreaktion wurde bei Ratten untersucht, denen intratracheal Kohlenstoffnanopartikel zugeführt wurden. Dies geschah sowohl zusammen mit als auch ohne Ectoin. Anschließend wurden die Ratten zu verschiedenen Zeitpunkten untersucht, wobei man nach zwei Tagen eine signifikante Reduzierung der Zahl an Neutrophilen in der Ectoin-Gruppe im Vergleich zur Placebo-Gruppe beobachten konnte. Die Wirksamkeit nach zwei Tagen ist in Übereinstimmung mit der beobachteten Reduzierung der cinc-1-Freisetzung, eines Chemokins, das bei Entzündungen eine wichtige Rolle spielt. Zunächst erfolgt die Freisetzung des cinc-1 in erster Linie durch Epithelzellen und Makrophagen, während zu späteren Zeitpunkten die Freisetzung durch die letztlich in hoher Zahl vorhandenen Neutrophile dominiert. Die Reduzierung der cinc-1-Freisetzung nach zwei Tagen bei Ectoin-Verabreichung zeigt, dass zu diesem Zeitpunkt die Zahl der Neutrophile abgenommen hat.The neutrophil inflammatory response was studied in rats fed with intratracheal carbon nanoparticles. This happened both together with and without Ectoin. Subsequently, the rats were examined at different times, with a significant reduction in the number of neutrophils in the ectoine group compared to the placebo group observed after two days. The efficacy after two days is consistent with the observed reduction in cinc-1 release, a chemokine that plays an important role in inflammation. Initially, the release of cinc-1 occurs primarily through epithelial cells and macrophages, while at later times the release is dominated by the neutrophils, which are ultimately abundant. The reduction in cinc-1 release after two days of ectoine administration indicates that the number of neutrophils has decreased by this time.
Ebenso konnte gezeigt werden, dass die Gabe von Ectoin in zwei Dosen 1 und 2 Tage nach Auslösung der Entzündungsreaktion praktisch denselben Effekt hat wie die Verabreichung des Ectoins bei Auslösung der Entzündungsreaktion. Ectoin kann somit nicht nur präventiv, sondern auch zur Behandlung einer bereits vorliegenden Entzündung eingesetzt werden. Auch bei wiederholter Gabe von Ectoin nach mehrfacher Auslösung einer Entzündungsreaktion konnte eine Reduzierung der Zahl an Neutrophilen sowie eine Absenkung des cinc-1-Niveaus beobachtet werden, was die Anwendbarkeit bei der Behandlung von chronischen Entzündungen unterstreicht.It was also shown that the administration of ectoine in two doses 1 and 2 days after initiation of the inflammatory reaction has practically the same effect as the administration of ectoine when the inflammatory reaction is triggered. Ectoin can thus be used not only preventively, but also for the treatment of an existing inflammation. Even repeated injections of ectoine after multiple inflammatory reactions have shown a reduction in the number of neutrophils and a decrease in cinc-1 levels, highlighting its applicability in the treatment of chronic inflammation.
Entsprechende Untersuchungen wurden auch mit isolierten humanen neutrophilen Granulozyten durchgeführt. Es konnte gezeigt werden, dass die Absenkung der Apoptoserate durch pro-entzündliche Faktoren wie Kohlenstoffnanopartikel (CNP), LTB4 oder GM-CSF durch Gabe von Ectoin konzentrationsabhängig zumindest partiell kompensierbar ist. Die Gabe von Ectoin allein zu den Neutrophilen ohne vorherige Behandlung mit proentzündlichen Faktoren führte nicht zu einer Erhöhung der Apoptoserate. Dies zeigt, dass Ectoin nicht grundsätzlich pro-apoptotisch wirkt, sondern vielmehr die bei einer Entzündung ablaufenden anti-apoptotischen Mechanismen unterdrückt.Corresponding investigations were also carried out with isolated human neutrophilic granulocytes. It could be shown that the lowering of the apoptosis rate by pro-inflammatory factors such as carbon nanoparticles (CNP), LTB 4 or GM-CSF by the administration of ectoine is at least partially compensated by concentration. The administration of ectoine alone to the neutrophils without prior treatment with pro-inflammatory factors did not increase the rate of apoptosis. This shows that Ectoin is not basically pro-apoptotic, but rather suppresses the anti-apoptotic mechanisms involved in inflammation.
Die anti-anti-apoptotische Wirksamkeit wurde zwar anhand von Versuchen in vivo und in vitro nachgewiesen, bei denen eine Entzündungsreaktion mithilfe von Kohlenstoffnanopartikeln ausgelöst wurde, sie ist jedoch hierauf nicht beschränkt, vielmehr betrifft die vorliegende Erfindung explizit gerade auch solche Entzündungen, die nicht auf Schwebstaubeinwirkung zurückzuführen sind. Während die
Als besonders vorteilhaft hat sich darüber hinaus eine Kombination von Ectoin/Hydroxyectoin bzw. entsprechender Derivate mit Corticosteroiden erwiesen, insbesondere mit Glucocorticoiden wie Dexamethason, Betamethason, Triamcinolon, Fluocortolon, Methylprednisolon, Deflazacort, Prednisolon, Prednison, Cloprednol, Cortison, Hydrocortison, Fluocortin, Clocortolon, Clobetason, Alclomethason, Flumethason, Fluopredniden, Fluorandrenolon, Prednicarbat, Mometason, Methylprednisolon, Fluticason, Halomethason, Fluocinolon, Diflorasan, Desoximethason, Fluocinonid, Fludrocortison, Deflazacort, Rimexolon, Cloprednol, Amcinonid, Halcinonid, Diflucortolon, Clobetasol oder Salzen, Estern, Amiden, Solvaten oder Hydraten dieser Verbindungen. In addition, a combination of ectoine / hydroxyectoine or corresponding derivatives with corticosteroids has proven particularly advantageous, in particular with glucocorticoids such as dexamethasone, betamethasone, triamcinolone, fluocortolone, methylprednisolone, deflazacort, prednisolone, prednisone, cloprednol, cortisone, hydrocortisone, fluocortin ,locortolone , Clobetasone, alclomethasone, flumethasone, fluopredniden, fluorandrenolone, prednicarbate, mometasone, methylprednisolone, fluticasone, halomethasone, fluocinolone, diflorasan, desoximethasone, fluocinonide, fludrocortisone, deflazacort, rimexolone, cloprednol, amcinonide, halcinonide, diflucortolone, clobetasol or salts, esters, amides , Solvates or hydrates of these compounds.
Obgleich Corticosteroide als wirksame Mittel gegen Entzündungen bekannt sind, spielen sie bei der Bekämpfung von neutrophilen Entzündungen eine zweischneidige Rolle, da sie die natürliche neutrophile Apoptose herabsetzen. Durch Kombination eines Corticosteroids mit Ectoin/Hydroxyectoin wird daher die vorteilhafte antientzündliche Wirkung des Steroids mit der Restauration der natürlichen Apoptoserate und somit Reduktion der unerwünschten anti-apoptotischen Wirkung des Corticosteroids durch Ectoin/Hydroxyectoin kombiniert. Alternative vorteilhafte Kombinationen sind Ectoin/Hydroxyectoin mit GM-CSF, Leukotrienen wie LTB4, Theophyllin (1,3-Dimethyl-xanthin), Leukotrienantagonisten, Phosphodiesterase-Hemmer (PDE-Hemmer, insbesondere PDE4-Hemmer), Muskarinrezeptor-Antagonisten, Anticholinergika wie Ipratropiumbromid oder Tiotropiumbromid oder anderen Arzneistoffen, bei denen die natürliche neutrophile Apoptoserate unerwünscht herabgesetzt wird.Although corticosteroids are known to be effective in the treatment of inflammation, they play a dual role in the control of neutrophilic inflammation because they reduce natural neutrophilic apoptosis. By combining a corticosteroid with ectoine / hydroxyectoine, therefore, the beneficial anti-inflammatory effect of the steroid is combined with the restoration of the natural apoptosis rate and thus reduction of the undesirable anti-apoptotic effect of the corticosteroid by ectoine / hydroxyectoine. Alternative advantageous combinations are ectoine / hydroxyectoine with GM-CSF, leukotrienes such as LTB 4 , theophylline (1,3-dimethyl-xanthine), leukotriene antagonists, phosphodiesterase inhibitors (PDE inhibitors, in particular PDE4 inhibitors), muscarine receptor antagonists, anticholinergics such as Ipratropium bromide or tiotropium bromide or other drugs in which the natural rate of neutrophil apoptosis is undesirably reduced.
Besondere Bedeutung hat auch bei einer Kombination von Corticosteroiden mit Ectoin/Hydroxyectoin die Behandlung von Lungenerkrankungen, insbesondere Lungenentzündungen, Asthma (Asthma bronchiale), chronisch obstruktiven Lungenerkrankungen (COPD), ARDS, zystischer Fibrose, Lungenfibrose, Silikose, Sarkoidose, Allergien und bronchialer Hyperreagibilität. Sinnvoll ist es dabei, die Zusammensetzung als inhalierbare Zusammensetzung vorzusehen. Die Zusammensetzung kann dabei flüssig als Lösung oder fest vorliegen, wobei die Zusammensetzung zweckmäßigerweise bei Bedarf mit Hilfe einer Inhalationsvorrichtung als Aerosol zerstäubt und eingeatmet wird.Also of particular importance in a combination of corticosteroids with ectoine / hydroxyectoine is the treatment of lung diseases, in particular pneumonia, asthma (bronchial asthma), chronic obstructive pulmonary diseases (COPD), ARDS, cystic fibrosis, pulmonary fibrosis, silicosis, sarcoidosis, allergies and bronchial hyperreactivity. It makes sense to provide the composition as an inhalable composition. The composition may be liquid as a solution or solid, wherein the composition is expediently atomized and inhaled as needed using an inhalation device as an aerosol.
Die Verabreichung von Corticosteroiden und Ectoin/Hydroxyectoin muss nicht in jedem Fall aus derselben Zusammensetzung heraus erfolgen, wichtig ist jedoch die gleichzeitige oder zeitnahe Verabreichung, so dass die Wirkstoffe funktionell in der oben beschriebenen Weise zusammenwirken. Entsprechend betrifft die Erfindung auch ein Kombinationspräparat, das zumindest zwei einzelne Zusammensetzungen umfasst, nämlich eine Zusammensetzung enthaltend Ectoin, Hydroxyectoin und/oder ein Salz, Ester oder Amid dieser Verbindungen sowie eine weitere Zusammensetzung, die ein Corticosteroid enthält. Das Kombinationspräparat stellt somit ein Kit of Parts aus zwei Zusammensetzungen dar, die erst gemeinsam ihre volle Wirksamkeit entfalten. Bei dem Corticosteroid kann es sich insbesondere um eines der oben genannten Glucocorticoide handeln.The administration of corticosteroids and ectoine / hydroxyectin need not always be from the same composition, but it is important to administer them simultaneously or in a timely manner so that the active ingredients functionally interact in the manner described above. Accordingly, the invention also relates to a combination preparation comprising at least two individual compositions, namely a composition containing ectoine, hydroxyectoine and / or a salt, ester or amide of these compounds and a further composition containing a corticosteroid. The combination preparation thus represents a kit of parts of two compositions, which only develop their full effectiveness together. The corticosteroid may in particular be one of the above-mentioned glucocorticoids.
Als pharmakologisch verträgliche Salze des Ectoins/Hydroxyectoins kommen die Alkali- oder Erdalkalisalze, insbesondere die Salze des Kaliums, Natriums, Magnesiums und Calciums, aber auch Salze mit organischen Basen wie z. B. mit nicht toxischen aliphatischen oder aromatischen Aminen in Frage.As a pharmacologically acceptable salts of ectoine / hydroxyectoins are the alkali or alkaline earth metal salts, especially the salts of potassium, sodium, magnesium and calcium, but also salts with organic bases such. B. with non-toxic aliphatic or aromatic amines in question.
Durch Umsetzung der Carboxylgruppe des Ectoins/Hydroxyectoins mit Alkoholen oder Aminen, können entsprechende Ester oder Amide erhalten werden, die ebenfalls erfindungsgemäß einsetzbar sind. Im Falle eines Amids kann das Stickstoffatom wiederum gesättigte oder ungesättigte, geradkettige oder verzweigte Alkylgruppen aufweisen. Beim Hydroxyectoin kann auch die Hydroxygruppe mit einer Carbonsäure zu einem entsprechenden Ester umgesetzt sein.By reacting the carboxyl group of ectoine / hydroxyectoine with alcohols or amines, it is possible to obtain corresponding esters or amides which can likewise be used according to the invention. In the case of an amide, the nitrogen atom may again have saturated or unsaturated, straight-chain or branched alkyl groups. In hydroxyectoine, the hydroxy group may also be reacted with a carboxylic acid to give a corresponding ester.
Allgemein können die erfindungsgemäßen Wirkstoffe ggf. auch mit weiteren Wirkstoffen unter Einsatz von pharmakologisch unbedenklichen Hilfs- und Zusatzstoffen zu vorzugsweise inhalierbaren Arzneimitteln verarbeitet werden. Solche Zusätze sind bei inhalierbaren flüssigen Zubereitungen in erster Linie Wasser, ggf. unter Zusatz von weiteren Lösungsmitteln, Stabilisatoren, Konservierungsmitteln, Emulgatoren, Antioxidantien, Füllstoffen oder Lösungsvermittlern. Als weitere Wirkstoffe sind Antiasthmatika, Broncholytika, nichtsteroidale antientzündliche Stoffe (NSAIDs) oder Expektorantia denkbar. Als Konservierungsmittel kommen in Frage: Benzalkoniumchlorid, Chlorbutanol, Thiomersal, Methylparaben, Propylparaben, Sorbinsäure und deren Salze, Natriumedetat, Phenylethylalkohol, Chlohexidinhydrochloridacetat, -digluconat, Cetylpyridiniumchlorid, -bromid, Chlorkresol, Phenylquecksilberacetat, Phenylquecksilbernitrat, Phenylquecksilberborat, Phenoxyethanol.In general, the active compounds according to the invention can optionally also be processed with further active ingredients using pharmacologically acceptable auxiliaries and additives to preferably inhalable medicaments. Such additives are in the case of inhalable liquid preparations primarily water, optionally with the addition of further solvents, stabilizers, preservatives, emulsifiers, antioxidants, fillers or solubilizers. Other active substances are antiasthmatics, broncholytics, non-steroidal anti-inflammatory substances (NSAIDs) or expectorants. Suitable preservatives are: benzalkonium chloride, chlorobutanol, thiomersal, methylparaben, propylparaben, sorbic acid and its salts, sodium edetate, phenylethyl alcohol, chlohexidine hydrochloride acetate, digluconate, cetylpyridinium chloride, bromide, chlorocresol, phenylmercuric acetate, phenylmercuric nitrate, phenylmercuric borate, phenoxyethanol.
Die Formulierungen der Erfindung können ebenfalls geeignete Puffersysteme oder andere Hilfsstoffe zur pH-Einstellung beeinhalten, um einen pH-Wert einzustellen und aufrechtzuerhalten in der Größenordnung von 4–8, vorzugsweise von 5 bis 7,5. Geeignete Puffersysteme sind Citrat, Phosphat, Trometamol, Glycin, Borat, Acetat. Diese Puffersysteme können hergestellt werden aus Substanzen wie Citronensäure, Mononatriumphosphat, Dinatriumphosphat, Glycin, Borsäure, Natriumtetraborat, Essigsäure oder Natriumactat.The formulations of the invention may also include suitable buffering or other pH adjuvant adjuvants to adjust and maintain a pH of the order of 4-8, preferably from 5 to 7.5. Suitable buffer systems are citrate, phosphate, trometamol, glycine, borate, acetate. These buffer systems can be prepared from substances such as citric acid, monosodium phosphate, disodium phosphate, glycine, boric acid, sodium tetraborate, acetic acid or sodium lactate.
Die Konzentration des Ectoins/Hydroxyectoins bezogen auf die Zusammensetzung beträgt typischerweise 0,001 bis 50 Gew.-%, bevorzugt 0,05 bis 20 Gew.-%, insbesondere 0,1 bis 10 Gew.-%. The concentration of ectoine / hydroxyectoine with respect to the composition is typically from 0.001 to 50% by weight, preferably from 0.05 to 20% by weight, in particular from 0.1 to 10% by weight.
Im Fall der Verabreichung in fester Form, bspw. mittels Pulverinhalatoren, ist es sinnvoll, nur leicht resorbierbare nichtreizende Trägerstoffe wie mikronisierte Lactose einzusetzen.In the case of administration in solid form, for example by means of powder inhalers, it makes sense to use only slightly absorbable non-irritating carriers such as micronized lactose.
Versuch 1Trial 1
Kohlenstoffnanopartikel (CNP, 14 nm, Printex 90, Degussa, Frankfurt, Deutschland) wurden mit Hilfe einer Ultraschallbehandlung in einer phosphatgepufferten Salzlösung (PBS) suspendiert. Ebenso wurde eine 0,1 und eine 1 mM-Lösung von Ectoin in PBS hergestellt. Weibliche Fisher 344 Ratten wurden intratracheal mit 0,4 ml der CNP-Partikelsuspension behandelt. Nach 1 und 2 Tagen fand eine Behandlung mit 0,4 ml der Ectoin-Lösungen bzw. PBS statt. Am 3. Tag wurden die Ratten getötet, die Lungen wurden mit je 4 × 5 ml PBS gespült. Die Zellen jedes Tieres wurden in 1 ml PBS suspendiert und zentrifugiert. Die Pellets wurden 1 mal mit PBS gewaschen und in 300 μl hypotonischer Lösung (0,1% Natriumzitrat, 0,1% Triton × 100) enthaltend 50 μg/ml Propidiumiodid (PI) resuspendiert. Anschließend erfolgte die Fluoreszenzmessung zur Bestimmung der Apoptoserate.Carbon nanoparticles (CNP, 14 nm, Printex 90, Degussa, Frankfurt, Germany) were suspended in a phosphate buffered saline (PBS) by sonication. Similarly, a 0.1 and a 1 mM solution of ectoine in PBS was prepared. Female Fisher 344 rats were treated intratracheally with 0.4 ml of the CNP particle suspension. After 1 and 2 days, treatment with 0.4 ml of the Ectoin solutions or PBS took place. On the 3rd day, the rats were sacrificed, the lungs were rinsed with 4 x 5 ml PBS. The cells of each animal were suspended in 1 ml of PBS and centrifuged. The pellets were washed once with PBS and resuspended in 300 μl hypotonic solution (0.1% sodium citrate, 0.1% Triton x 100) containing 50 μg / ml propidium iodide (PI). Subsequently, the fluorescence measurement was carried out to determine the apoptosis rate.
Man erhielt das in
Versuch 2Trial 2
Die Wirkung von Ectoin auf die Apoptose wurde anhand von menschlichen Neutrophilen untersucht. Neutrophile von 3 männlichen und 2 weiblichen jungen, gesunden Spendern wurden isoliert und mit den angegebenen Mengen Ectoin (mM) behandelt. Die Behandlung erfolgte mit Ectoin allein (offene Balken) bzw. mit 33 μg/ml CNP (schwarze Balken). In der Kontrollgruppe (C) wurde kein Ectoin verabreicht. Das Ergebnis ist in
Die Quantifizierung der apoptotischen Zellen erfolgte in folgender Weise: Die Neutrophile wurden in 300 μl hypotonischer Lösung enthaltend Propidiumiodid (PI) suspendiert. Die Fluoreszenz von PI wurde über Durchflusszytometrie gemessen (FACScan Zytometer, BD Biosciences). Die Ergebnisse werden dargestellt als Prozentsatz an hypodiploider DNA (sub-G1), korrespondierend zur fragmentierten DNA, die für apoptotische Zellen charakteristisch ist.The quantification of the apoptotic cells was carried out in the following way: The neutrophils were suspended in 300 μl hypotonic solution containing propidium iodide (PI). The fluorescence of PI was measured by flow cytometry (FACScan cytometer, BD Biosciences). The results are presented as a percentage of hypodiploid DNA (sub-G1), corresponding to the fragmented DNA characteristic of apoptotic cells.
Die durch CNP hervorgerufene Reduktion der Apoptoserate konnte durch Verabreichung signifikanter Mengen Ectoin praktisch aufgehoben werden.The CNP-induced reduction in apoptosis rate was practically abolished by administration of significant amounts of ectoine.
(*: signifikanter Unterschied zur Kontrollgruppe ohne CNP-Behandlung; ✝: signifikanter Unterschied zu nur mit CNP und PBS behandelten Neutrophilen).(*: significant difference to control group without CNP treatment; ✝: significant difference to CNP and PBS treated neutrophils only).
Versuch 3Trial 3
Die Wirkung von Ectoin auf die Apoptose wurde anhand von menschlichen Neutrophilen untersucht. Neutrophile von 3 männlichen und 2 weiblichen jungen, gesunden Spendern wurden isoliert und für 2 h mit PBS (dunkle Balken) bzw. mit 1 mM Ectoin (helle Balken) vorbehandelt. Anschließend erfolgte die Behandlung mit 33 μg/ml Kohlenstoffnanopartikeln (ufCB: ultrafine carbon black), 300 nM LTB4, 20 ng/ml GM-CSF oder 1 μM Dexamethason bzw. keine Behandlung mit pro-entzündlichen Faktoren. Das Ergebnis ist in
Versuch 4Trial 4
Die Wirkung von Ectoin auf die Apoptose wurde analog zu Versuch 3 bei COPD-Patienten und entsprechend alten Nicht-COPD-Patienten nachgewiesen. Die neutrophilen Granulozyten wurden für 2 h mit 1 mM Ectoin bzw. PBS vorbehandelt, anschließend folgte Behandlung für 16 h mit 33 μg/ml CNP, 300 nM LTB4, 20 ng/ml GM-CSF oder PBS. Es konnte eine höhere Basis-Apoptose festgestellt werden, dennoch reduzierten die inflammatorischen Stimulantien die Apoptose und eine zusätzliche Behandlung mit Ectoin restaurierte die Apoptoserate signifikant. Das Ergebnis ist in
ZITATE ENTHALTEN IN DER BESCHREIBUNG QUOTES INCLUDE IN THE DESCRIPTION
Diese Liste der vom Anmelder aufgeführten Dokumente wurde automatisiert erzeugt und ist ausschließlich zur besseren Information des Lesers aufgenommen. Die Liste ist nicht Bestandteil der deutschen Patent- bzw. Gebrauchsmusteranmeldung. Das DPMA übernimmt keinerlei Haftung für etwaige Fehler oder Auslassungen.This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.
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- Da Costa, Santos, Galinski, Adv. in Biochemical Engineering Biotechnology, 61, 117–153 [0002] Da Costa, Santos, Galinski, Adv. In Biochemical Engineering Biotechnology, 61, 117-153 [0002]
Claims (12)
Priority Applications (16)
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DE102011113059A DE102011113059A1 (en) | 2011-09-09 | 2011-09-09 | Therapeutic Applications of Ectoin |
BR112014005414A BR112014005414A2 (en) | 2011-09-09 | 2012-09-07 | therapeutic applications of ectoin |
PL17189829T PL3287131T3 (en) | 2011-09-09 | 2012-09-07 | Therapeutic uses of ectoine |
PL12780649T PL2753330T3 (en) | 2011-09-09 | 2012-09-07 | Therapeutic uses of ectoin |
EP12780649.5A EP2753330B1 (en) | 2011-09-09 | 2012-09-07 | Therapeutic uses of ectoin |
CN201280049557.3A CN103857394A (en) | 2011-09-09 | 2012-09-07 | Therapeutic uses of ectoin |
IN2458CHN2014 IN2014CN02458A (en) | 2011-09-09 | 2012-09-07 | |
ES12780649.5T ES2657907T3 (en) | 2011-09-09 | 2012-09-07 | Therapeutic applications of ectoin |
US14/343,017 US20140315869A1 (en) | 2011-09-09 | 2012-09-07 | Therapeutic uses of ectoine |
CA2848010A CA2848010A1 (en) | 2011-09-09 | 2012-09-07 | Therapeutic applications of ectoine |
ES17189829T ES2795879T3 (en) | 2011-09-09 | 2012-09-07 | Therapeutic applications of ectoin |
RU2014113906A RU2648475C2 (en) | 2011-09-09 | 2012-09-07 | Therapeutic use of ektoin |
PCT/EP2012/003757 WO2013034299A1 (en) | 2011-09-09 | 2012-09-07 | Therapeutic uses of ectoin |
EP17189829.9A EP3287131B1 (en) | 2011-09-09 | 2012-09-07 | Therapeutic uses of ectoine |
JP2014528897A JP6250542B2 (en) | 2011-09-09 | 2012-09-07 | Therapeutic use of ectoine |
JP2017133770A JP6396544B2 (en) | 2011-09-09 | 2017-07-07 | Therapeutic use of ectoine |
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Application Number | Priority Date | Filing Date | Title |
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DE102011113059A DE102011113059A1 (en) | 2011-09-09 | 2011-09-09 | Therapeutic Applications of Ectoin |
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DE102011113059A1 true DE102011113059A1 (en) | 2013-03-14 |
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US (1) | US20140315869A1 (en) |
EP (2) | EP3287131B1 (en) |
JP (2) | JP6250542B2 (en) |
CN (1) | CN103857394A (en) |
BR (1) | BR112014005414A2 (en) |
CA (1) | CA2848010A1 (en) |
DE (1) | DE102011113059A1 (en) |
ES (2) | ES2795879T3 (en) |
IN (1) | IN2014CN02458A (en) |
PL (2) | PL3287131T3 (en) |
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US20160106747A1 (en) * | 2008-01-30 | 2016-04-21 | Bitop Ag | Treating postoperative mechanical stress with an ectoine |
DE102008039231A1 (en) | 2008-08-22 | 2010-02-25 | Bitop Ag | Use of glucosylglycerol |
DE102014007423A1 (en) * | 2014-05-22 | 2015-11-26 | Bitop Ag | Composition for the treatment of the eye |
DE102014113781A1 (en) * | 2014-09-23 | 2016-03-24 | Bitop Ag | Solut and solute mixture and a composition containing at least one solute for use in the prevention or treatment of induced by suspended particulate cosmetic or pathological Effloreszenzen |
DE102015121050A1 (en) * | 2015-12-03 | 2017-06-08 | Bitop Ag | A compatible solute or solute mixture for use in the prevention or treatment of diseases with barrier defects in epithelial tissues |
DE102016104470A1 (en) | 2016-03-11 | 2017-09-14 | Bitop Ag | Composition for promoting the activity of sirtuins |
CN111936142A (en) * | 2018-04-05 | 2020-11-13 | 株式会社资生堂 | ASMT expression promoter |
CN114425056A (en) * | 2020-10-14 | 2022-05-03 | 宁波希诺赛生物科技有限公司 | Stem cell exosome composition for improving asthma |
Citations (5)
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EP0887418A2 (en) | 1992-12-31 | 1998-12-30 | bitop Gesellschaft für biotechnische Optimierung mbH | In vivo method of obtaining cell components |
DE10065986A1 (en) | 2000-12-21 | 2002-07-11 | Bitop Gmbh | Pharmaceutical formulation, especially a vaccine, e.g. against polio or parvovirus, contains proteins, peptides and/or nucleic acids as well as compatible solutes |
DE10330243A1 (en) | 2003-07-03 | 2005-01-20 | bitop Aktiengesellschaft für biotechnische Optimierung | Use of osmolytes derived from extremophilic bacteria for the manufacture of medicines for the external treatment of atopic dermatitis |
DE102006056766A1 (en) | 2006-12-01 | 2008-06-05 | Bitop Ag | Use of compatible solutes |
EP1641442B1 (en) | 2003-07-07 | 2010-09-15 | Bitop Aktiengesellschaft Für Biotechnische Optimierung | Use of ectoine and/or hydroxyectoine for the production of inhalable medicaments and an inhalation device comprising this agent |
Family Cites Families (5)
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DE4342560A1 (en) * | 1993-12-14 | 1995-06-22 | Marbert Gmbh | Use of 1,4,5,6-tetra:hydro-4-pyrimidine carboxylic acid derivs. in cosmetics |
WO2000036915A1 (en) * | 1998-12-22 | 2000-06-29 | The University Of North Carolina At Chapel Hill | Compounds and methods for the treatment of airway diseases and for the delivery of airway drugs |
AU5812800A (en) * | 1999-06-12 | 2001-01-02 | Stefan Barth | Pharmaceutical preparation |
DE10006578C2 (en) * | 2000-02-14 | 2002-10-31 | Bitop Ag | Use of compatible solutes as inhibitors of the enzymatic degradation of macromolecular biopolymers |
DE102007040615A1 (en) * | 2007-08-27 | 2009-03-05 | Bitop Ag | Osmolyte for the treatment of allergic or viral respiratory diseases |
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2011
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2012
- 2012-09-07 IN IN2458CHN2014 patent/IN2014CN02458A/en unknown
- 2012-09-07 RU RU2014113906A patent/RU2648475C2/en not_active IP Right Cessation
- 2012-09-07 CA CA2848010A patent/CA2848010A1/en not_active Abandoned
- 2012-09-07 CN CN201280049557.3A patent/CN103857394A/en active Pending
- 2012-09-07 US US14/343,017 patent/US20140315869A1/en not_active Abandoned
- 2012-09-07 PL PL17189829T patent/PL3287131T3/en unknown
- 2012-09-07 EP EP17189829.9A patent/EP3287131B1/en active Active
- 2012-09-07 JP JP2014528897A patent/JP6250542B2/en active Active
- 2012-09-07 BR BR112014005414A patent/BR112014005414A2/en not_active Application Discontinuation
- 2012-09-07 WO PCT/EP2012/003757 patent/WO2013034299A1/en active Application Filing
- 2012-09-07 ES ES17189829T patent/ES2795879T3/en active Active
- 2012-09-07 ES ES12780649.5T patent/ES2657907T3/en active Active
- 2012-09-07 EP EP12780649.5A patent/EP2753330B1/en active Active
- 2012-09-07 PL PL12780649T patent/PL2753330T3/en unknown
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2017
- 2017-07-07 JP JP2017133770A patent/JP6396544B2/en active Active
Patent Citations (5)
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EP0887418A2 (en) | 1992-12-31 | 1998-12-30 | bitop Gesellschaft für biotechnische Optimierung mbH | In vivo method of obtaining cell components |
DE10065986A1 (en) | 2000-12-21 | 2002-07-11 | Bitop Gmbh | Pharmaceutical formulation, especially a vaccine, e.g. against polio or parvovirus, contains proteins, peptides and/or nucleic acids as well as compatible solutes |
DE10330243A1 (en) | 2003-07-03 | 2005-01-20 | bitop Aktiengesellschaft für biotechnische Optimierung | Use of osmolytes derived from extremophilic bacteria for the manufacture of medicines for the external treatment of atopic dermatitis |
EP1641442B1 (en) | 2003-07-07 | 2010-09-15 | Bitop Aktiengesellschaft Für Biotechnische Optimierung | Use of ectoine and/or hydroxyectoine for the production of inhalable medicaments and an inhalation device comprising this agent |
DE102006056766A1 (en) | 2006-12-01 | 2008-06-05 | Bitop Ag | Use of compatible solutes |
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Title |
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Da Costa, Santos, Galinski, Adv. in Biochemical Engineering Biotechnology, 61, 117-153 |
K. Lippert, E. A. Galinski, Appl. Microbiol. Biotech. 1992, 37, 61-65 |
P. Louis, H. G. Trüper, E. A. Galinski, Appl. Microbiol. Biotech. 1994, 41, 684-688 |
Ramos et al., Appl. Environm. Microbiol. 1997, 63, 4020-4025 |
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JP6396544B2 (en) | 2018-09-26 |
BR112014005414A2 (en) | 2017-04-04 |
EP2753330A1 (en) | 2014-07-16 |
PL3287131T3 (en) | 2020-10-19 |
EP2753330B1 (en) | 2017-11-08 |
ES2657907T3 (en) | 2018-03-07 |
JP6250542B2 (en) | 2017-12-20 |
EP3287131A1 (en) | 2018-02-28 |
CA2848010A1 (en) | 2013-03-14 |
US20140315869A1 (en) | 2014-10-23 |
JP2017197569A (en) | 2017-11-02 |
ES2795879T3 (en) | 2020-11-25 |
RU2648475C2 (en) | 2018-03-26 |
PL2753330T3 (en) | 2018-05-30 |
IN2014CN02458A (en) | 2015-08-07 |
CN103857394A (en) | 2014-06-11 |
WO2013034299A1 (en) | 2013-03-14 |
JP2014526448A (en) | 2014-10-06 |
RU2014113906A (en) | 2015-10-20 |
EP3287131B1 (en) | 2020-03-04 |
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